Comprehensive value implications of surgeon volume for lung cancer surgery: Use of an analytic framework within a regional health system.

Objective: We used a framework to assess the value implications of thoracic surgeon operative volume within an 8-hospital health system. Methods: Surgical cases for non-small cell lung cancer were assessed from March 2015 to March 2021. High-volume (HV) surgeons performed >25 pulmonary resections annually. Metrics include length of stay, infection rates, 30-day readmission, in-hospital mortality, median 30-day charges and direct costs, and 3-year recurrence-free and overall survival. Multivariate regression-based propensity scores matched patients between groups. Metrics were graphed on radar charts to conceptualize total value. Results: All 638 lung resections were performed by 12 surgeons across 6 hospitals. Two HV surgeons performed 51% (n = 324) of operations, and 10 low-volume surgeons performed 49% (n = 314). Median follow-up was 28.8 months (14.0-42.3 months). Lobectomy was performed in 71% (n = 450) of cases. HV surgeons performed more segmentectomies (33% [n = 107] vs 3% [n = 8]; P < .001). Patients of HV surgeons had a lower length of stay (3 [2-4] vs 5 [3-7]; P < .001) and infection rates (0.6% [n = 1] vs 4% [n = 7]; P = .03). Low-volume and HV surgeons had similar 30-day readmission rates (14% [n = 23] vs 7% [n = 12]; P = .12), in-hospital mortality (0% [n = 0] vs 0.6% [n = 1]; P = .33), and oncologic outcomes; 3-year recurrence-free survival was 95% versus 91%; P = .44, and 3-year overall survival was 94% versus 90%; P = 0. Charges were reduced by 28%, and direct costs were reduced by 23% (both P < .001) in the HV cohort. Conclusions: HV surgeons provide comprehensive value across a health system. This multidomain framework can be used to help drive oncologic care decisions within a health system.

Surveillance Mammography After Breast Conservation Therapy: Is Tomosynthesis Worth It?

INTRODUCTION: We investigated the downstream workup and costs associated with digital breast tomosynthesis (DBT) compared with 2-dimensional full field digital mammogram (FFDM) when employed as initial follow-up imaging in breast conservation therapy. METHODS: Between the years 2015 and 2017, 450 consecutive breast conservation therapy patients, ages 32 to 89, with a follow-up DBT (n=162) or FFDM (n=288) were retrospectively reviewed. The primary endpoints were further workup after follow-up mammogram and associated health care costs at 1 year. A single DBT costs an estimated $149 compared with $111 for FFDM, based on Centers for Medicare claims data from the Oncology Care Model. RESULTS: The first posttreatment mammogram was received within 3 (20%), 3 to 6 (32%), or after 6 months (48%) following radiation. Younger patients and those undergoing hypofractionated radiation were more likely to get DBT. There were no differences in stage, receptor status, or mammogram timing between those in the FFDM and DBT groups.The following downstream workup ensued for DBT compared with FFDM imaging: 18% versus 29% short-interval (6-mo) mammogram (odds ratio=1.83, P=0.01), 6% versus 11% breast magnetic resonance imaging (odds ratio=1.90, P=0.08), 4% ultrasound for each, and 3% biopsy for each (1 positive in the FFDM group). Including downstream workup, the estimated cost per patient in the DBT group was $216.14 compared with $237.83 in the FFDM group. Independent predictors for reduced downstream workup per multivariable analysis were the use of DBT and first follow-up mammogram at least 6 months after radiation (P<0.05). DISCUSSION: Excess workup was reduced with DBT compared with FFDM in the posttreatment setting, which translated to an improvement in cost efficiency in this study.

CD4 T cell depletion exacerbates acute Mycobacterium tuberculosis while reactivation of latent infection is dependent on severity of tissue depletion in cynomolgus macaques.

CD4 T cells are believed to be important in protection against Mycobacterium tuberculosis, but the relative contribution to control of initial or latent infection is not known. Antibody-mediated depletion of CD4 T cells in M. tuberculosis-infected cynomolgus macaques was used to study the role of CD4 T cells during acute and latent infection. Anti-CD4 antibody severely reduced levels of CD4 T cells in blood, airways, and lymph nodes. Increased pathology and bacterial burden were observed in CD4-depleted monkeys during the first 8 weeks of infection compared to controls. CD4-depleted monkeys had greater interferon (IFN)-γ expression and altered expression of CD8 T cell activation markers. During latent infection, CD4 depletion resulted in clinical reactivation in only three of six monkeys. Reactivation was associated with lower CD4 T cells in the hilar lymph nodes. During both acute and latent infection, CD4 depletion was associated with reduced percentages of CXCR3(+) expressing CD8 T cells, reported to be involved in T cell recruitment, regulatory function, and effector and memory T cell maturation. CXCR3(+) CD8 T cells from hilar lymph nodes had more mycobacteria-specific cytokine expression and greater coexpression of multiple cytokines compared to CXCR3(-) CD8 T cells. CD4 T cells are required for protection against acute infection but reactivation from latent infection is dependent on the severity of depletion in the draining lymph nodes. CD4 depletion influences CD8 T cell function. This study has important implications for human HIV-M. tuberculosis coinfection.

The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection.

It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress-induced antigen Rv2660c. Boosting with H56/IC31 resulted in efficient containment of M. tuberculosis infection and reduced rates of clinical disease, as measured by clinical parameters, inflammatory markers, and improved survival of the animals compared with BCG alone. Boosted animals showed reduced pulmonary pathology and extrapulmonary dissemination, and protection correlated with a strong recall response against ESAT-6 and Rv2660c. Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56.

Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model.

OBJECTIVE: An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor alpha (TNFalpha)-neutralizing agents. In murine models, impaired signaling by TNF causes exacerbation of both acute and chronic infection associated with aberrant granuloma formation and maintenance. This study was undertaken to investigate immune modulation in the setting of TNF neutralization in primary and latent tuberculosis in a non-human primate model. METHODS: Cynomolgus macaques 4 years of age or older were infected with Mycobacterium tuberculosis and subjected to clinical, microbiologic, immunologic, and radiographic examinations. Monkeys were classified as having active or latent disease 6-8 months after infection, based on clinical criteria. Monkeys used in acute infection studies were randomized to receive either adalimumab (prior to and during infection) or no treatment. Monkeys with latent infection that were randomized to receive TNF-neutralizing agent were given either an inhibitor of soluble TNF, recombinant methionyl human soluble TNF receptor I (p55-TNFRI), or adalimumab. Control monkeys with latent infection were given no treatment or saline. Data from previously studied monkeys with active or latent disease were also used for comparison. RESULTS: Administration of TNF-neutralizing agents prior to M tuberculosis infection resulted in fulminant and disseminated disease by 8 weeks after infection. Neutralization of TNF in latently infected cynomolgus macaques caused reactivation in a majority of animals as determined by gross pathologic examination and bacterial burden. A spectrum of dissemination was noted, including extrapulmonary disease. Surprisingly, monkeys that developed primary and reactivation tuberculosis after TNF neutralization had similar granuloma structure and composition to that of control monkeys with active disease. TNF neutralization was associated with increased levels of interleukin-12, decreased levels of CCL4, increased chemokine receptor expression, and reduced mycobacteria-induced interferon-gamma production in blood but not in the affected mediastinal lymph nodes. Finally, the first signs of reactivation often occurred in thoracic lymph nodes. CONCLUSION: These findings have important clinical implications for determining the mechanism of TNF neutralization-related tuberculosis.

Non-Steroidal Anti-Inflammatory Drugs in Alzheimer's Disease and Parkinson's Disease: Reconsidering the Role of Neuroinflammation.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases with age as the greatest risk factor. As the general population experiences extended life span, preparation for the prevention and treatment of these and other age-associated neurological diseases are warranted. Since epidemiological studies suggested that non-steroidal anti-inflammatory drug (NSAID) use decreased risk for AD and PD, increasing attention has been devoted to understanding the costs and benefits of the innate neuroinflammatory response to functional recovery following pathology onset. This review will provide a general overview on the role of neuroinflammation in these neurodegenerative diseases and an update on NSAID treatment in recent experimental animal models, epidemiological analyses, and clinical trials.

Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model.

We previously described that low-dose Mycobacterium tuberculosis infection in cynomolgus macaques results in a spectrum of disease similar to that of human infection: primary disease, latent infection, and reactivation tuberculosis (S. V. Capuano III, D. A. Croix, S. Pawar, A. Zinovik, A. Myers, P. L. Lin, S. Bissel, C. Fuhrman, E. Klein, and J. L. Flynn, Infect. Immun. 71:5831-5844, 2003). This is the only established model of latent infection, and it provides a unique opportunity to understand host and pathogen differences across of range of disease states. Here, we provide a more extensive and detailed characterization of the gross pathology, microscopic histopathology, and immunologic characteristics of monkeys in each clinical disease category. The data underscore the similarities between human and nonhuman primate M. tuberculosis infection. Furthermore, we describe novel methods of quantifying gross pathology and bacterial burden that distinguish between active disease and latent infection, and we extend the usefulness of this model for comparative studies. Early in infection, an abnormal chest X ray, M. tuberculosis growth by gastric aspirate, and increased mycobacterium-specific gamma interferon (IFN-gamma) in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage (BAL) cells were associated with the development of active disease. At necropsy, disease was quantified with respect to pathology and bacterial numbers. Microscopically, a spectrum of granuloma types are seen and differ with disease type. At necropsy, monkeys with active disease had more lung T cells and more IFN-gamma from PBMC, BAL, and mediastinal lymph nodes than monkeys with latent infection. Finally, we have observed a spectrum of disease not only in monkeys with active disease but also in those with latent infection that provides insight into human latent tuberculosis.